PubMed

Front Genet. 2023 Jan 30;14:1076421. doi: 10.3389/fgene.2023.1076421. eCollection 2023.ABSTRACTFrom the perspective of precision medicine, the challenge for the future is to improve the accuracy of diagnosis, prognosis, and prediction of therapeutic responses through the identification of biomarkers. In this framework, the omics sciences (genomics, transcriptomics, proteomics, and metabolomics) and their combined use represent innovative approaches for the exploration of the complexity and heterogeneity of multiple sclerosis (MS). This review examines the evidence currently available on the application of omics sciences to MS, analyses the methods, their limitations, the samples used, and their characteristics, with a particular focus on biomarkers associated with the disease state, exposure to disease-modifying treatments (DMTs), and drug efficacies and safety profiles.PMID:36793897 | PMC:PMC9922720 | DOI:10.3389/fgene.2023.1076421

Nanotheranostics. 2023 Jan 1;7(2):142-151. doi: 10.7150/ntno.79394. eCollection 2023.ABSTRACTBackground: Septic shock, with a prolonged hospital stay, has the highest mortality rate worldwide. There is a need for better management of the disease, which requires time-dependent analysis of alteration occurring in the disease condition and subsequent planning of treatment strategies to curb mortality. Objective: The study aims to identify early metabolic signatures associated with septic shock before treatment and post-treatment. It also entails the progression of patients towards recovery, which clinicians could use to analyze treatment efficacy. Methods: The study was performed on 157 serum samples of patients with septic shock. We performed metabolomic, univariate, and multivariate statistics to identify the significant metabolite signature of patients prior to treatment and during treatment by collecting serum samples on the day I, day III, and day V of treatment. Results: We identified metabotypes of patients before treatment and post-treatment. The study showed time-dependent metabolite alteration in ketone bodies, amino acids, choline, and NAG in patients undergoing treatment. Conclusion: This study illustrates the metabolite's journey in septic shock and during treatment, which may be of prospective assistance to clinicians to monitor therapeutics.PMID:36793353 | PMC:PMC9925348 | DOI:10.7150/ntno.79394

Cancer Sci. 2023 Feb 15. doi: 10.1111/cas.15760. Online ahead of print.ABSTRACTTumor associated macrophages (TAMs) are one of the most abundant immunosuppressive cells in the tumor microenvironment and possess crucial functions in facilitating tumor progression. Emerging evidences indicate that altered metabolic properties in cancer cell support the tumorigenic functions of TAMs. However, mechanisms and mediators underly crosstalk between cancer cell and TAMs remain largely unknown. In present study, we revealed that high Solute Carrier Family 3 Member 2 (SLC3A2) expression in lung cancer patients were associated with TAMs and poor prognosis. Knockdown of SLC3A2 in lung adenocarcinoma cells impaired M2 polarization of macrophages in co-culture system. By using metabolome analysis, we identified that knockdown SLC3A2 altered metabolism of lung cancer cells and changed multiple metabolites including arachidonic acid in the tumor microenvironment. More importantly, we demonstrated that arachidonic acid was responsible for SLC3A2 mediated macrophage polarization in the tumor microenvironment to differentiate into M2 type both in vitro and in vivo. Our data illustrate previously undescribed mechanisms responsible for TAMs polarization and suggest that SLC3A2 acts as a metabolic switch on lung adenocarcinoma cells to induce macrophage phenotypic reprogramming via arachidonic acid.PMID:36793241 | DOI:10.1111/cas.15760

New Phytol. 2023 Feb 15. doi: 10.1111/nph.18814. Online ahead of print.ABSTRACTQuercus dentata Thunb., a dominant forest tree species in northern China, has significant ecological and ornamental value due to its adaptability and beautiful autumn coloration, with color changes from green to yellow into red resulting from the autumnal shifts in leaf pigmentation. However, the key genes and molecular regulatory mechanisms for leaf color transition remain to be investigated. First, we presented a high-quality chromosome-scale assembly for Q. dentata. This 893.54 Mb sized genome (contig N50=4.21 Mb, scaffold N50=75.55 Mb; 2n=24) harbors 31,584 protein-coding genes. Second, our metabolome analyses uncovered pelargonidin-3-O-glucoside, cyanidin-3-O-arabinoside, and cyanidin-3-O-glucoside as the main pigments involved in leaf color transition. Third, gene co-expression further identified the MYB-bHLH-WD40 (MBW) transcription activation complex as central to anthocyanin biosynthesis regulation. Notably, transcription factor (TF) QdNAC (QD08G038820) was highly co-expressed with this MBW complex and may regulate anthocyanin accumulation and chlorophyll degradation during leaf senescence through direct interaction with another TF, QdMYB (QD01G020890), as revealed by our further protein-protein and DNA-protein interaction assays. Our high-quality genome assembly, metabolome and transcriptome resources further enrich Quercus genomics, and will facilitate upcoming exploration of ornamental values and environmental adaptability in this important genus.PMID:36792969 | DOI:10.1111/nph.18814

Sci Rep. 2023 Feb 15;13(1):2671. doi: 10.1038/s41598-023-29234-3.ABSTRACTEach year, bovine respiratory disease (BRD) results in significant economic loss in the cattle sector, and novel metabolic profiling for early diagnosis represents a promising tool for developing effective measures for disease management. Here, 1H-nuclear magnetic resonance (1H-NMR) spectra were used to characterize metabolites from blood plasma collected from male dairy calves (n = 10) intentionally infected with two of the main BRD causal agents, bovine respiratory syncytial virus (BRSV) and Mannheimia haemolytica (MH), to generate a well-defined metabolomic profile under controlled conditions. In response to infection, 46 metabolites (BRSV = 32, MH = 33) changed in concentration compared to the uninfected state. Fuel substrates and products exhibited a particularly strong effect, reflecting imbalances that occur during the immune response. Furthermore, 1H-NMR spectra from samples from the uninfected and infected stages were discriminated with an accuracy, sensitivity, and specificity ≥ 95% using chemometrics to model the changes associated with disease, suggesting that metabolic profiles can be used for further development, understanding, and validation of novel diagnostic tools.PMID:36792613 | DOI:10.1038/s41598-023-29234-3

Environ Pollut. 2023 Feb 13:121287. doi: 10.1016/j.envpol.2023.121287. Online ahead of print.ABSTRACTDetermining dose-response relationship is essential for comprehensively revealing chemical-caused effects on organisms. However, uncertainty and complexity of gene/protein interactions cause the inability of traditional toxicogenomic methods (e.g., transcriptomics, proteomics and metabolomics) to effectively establish the direct relationship between chemical exposure and genes. In this work, we built an effective dose-dependent yeast functional genomics approach, which can clearly identify the direct gene-chemical link in the process of cadmium (Cd) toxification from a genome-wide scale with wide range concentrations (0.83, 2.49, 7.48, 22.45, 67.34, 202.03 and 606.1 μM). Firstly, we identified 220 responsive strains, and found that 142, 110, 91, 34, 8, 0 and 0 responsive strains can be respectively modulated by seven different Cd exposure concentrations ranging from high to low. Secondly, our results demonstrated that these genes induced by the high Cd exposure were mainly enriched in the process of cell autophagy, but ones caused by the low Cd exposure were primarily involved in oxidative stress. Thirdly, we found that the top-ranked GO biological processes with the lowest point of departure (POD) were transmembrane transporter complex and mitochondrial respiratory chain complex III, suggesting that mitochondrion might be the toxicity target of Cd. Similarly, nucleotide excision repair was ranked first in KEGG pathway with the least POD, indicating that this dose-dependent functional genomics approach can effectively detect the molecular initiating event (MIE) of cadmium toxification. Fourthly, we identified four key mutant strains (RIP1, QCR8, CYT1 and QCR2) as biomarkers for Cd exposure. Finally, the dose-dependent functional genomics approach also performed well in identifying MIE for additional genotoxicity chemical 4-nitroquinoline-1-oxide (4-NQO) data. Overall, our study developed a dose-dependent functional genomics approach, which is powerful to delve into the MIE of chemical toxification and is beneficial for guiding further chemical risk assessment.PMID:36791950 | DOI:10.1016/j.envpol.2023.121287

Environ Pollut. 2023 Feb 13:121286. doi: 10.1016/j.envpol.2023.121286. Online ahead of print.ABSTRACTCadmium (Cd) contamination in marine environment poses great risks to the organisms due to its potential adverse effects. In the present study, the toxicological effects and mechanisms of Cd at environmentally relevant concentrations (5 and 50 μg/L) on clam Ruditapes philippinarum after 21 days were investigated by combined ionomic, metabolomic, and transcriptomic analyses. Results showed that the uptake of Cd significantly decreased the concentrations of Cu, Zn, Sr, Se, and Mo in the whole soft tissue from 50 μg/L Cd-treated clams. Significantly negative correlations were observed between Cd and essential elements (Zn, Sr, Se, and Mo). Altered essential elements homeostasis was associated with the gene regulation of transport and detoxification, including ATP-binding cassette protein subfamily B member 1 (ABCB1) and metallothioneins (MT). The crucial contribution of Se to Cd detoxification was also found in clams. Additionally, gene set enrichment analysis showed that Cd could interfere with proteolysis by peptidases and decrease the translation efficiency at 50 μg/L. Cd inhibited lipid metabolism in clams and increased energy demand by up-regulating glycolysis and TCA cycle. Osmotic pressure was regulated by free amino acids, including alanine, glutamate, taurine, and homarine. Meanwhile, significant alterations of some differentially expressed genes, such as dopamine-β-hydroxylase (DBH), neuroligin (NLGN), NOTCH 1, and chondroitin sulfate proteoglycan 1 (CSPG1) were observed in clams, which implied potential interference with synaptic transmission. Overall, through integrating multiple omics, this study provided new insights into the toxicological mechanisms of Cd, particularly in those mediated by dysregulation of essential element homeostasis.PMID:36791949 | DOI:10.1016/j.envpol.2023.121286

Brain Behav Immun. 2023 Feb 13:S0889-1591(23)00033-8. doi: 10.1016/j.bbi.2023.02.008. Online ahead of print.ABSTRACTAging is associated with remodelling of immune and central nervous system responses resulting in behavioural impairments including social deficits. Growing evidence suggests that the gut microbiome is also impacted by aging, and we propose that strategies to reshape the aged gut microbiome may ameliorate some age-related effects on host physiology. Thus, we assessed the impact of gut microbiota depletion, using an antibiotic cocktail, on aging and its impact on social behavior and the immune system. Indeed, microbiota depletion in aged mice eliminated the age-dependent deficits in social recognition. We further demonstrate that although age and gut microbiota depletion differently shape the peripheral immune response, aging induces an accumulation of T cells in the choroid plexus, that is partially blunted following microbiota depletion. Moreover, an untargeted metabolomic analysis revealed age-dependent alterations of cecal metabolites that are reshaped by gut microbiota depletion. Together, our results suggest that the aged gut microbiota can be specifically targeted to affect social deficits. These studies propel the need for future investigations of other non-antibiotic microbiota targeted interventions on age-related social deficits both in animal models and humans.PMID:36791892 | DOI:10.1016/j.bbi.2023.02.008

Sci Total Environ. 2023 Feb 13:162199. doi: 10.1016/j.scitotenv.2023.162199. Online ahead of print.ABSTRACTNitrofurans are broad-spectrum bactericidal agents used in a large quantity for veterinary and human therapy. This study reports the long-term impact of two nitrofuran representatives, nitrofurantoin (NFT) and furaltadone (FTD) on the bacterial strains Sphingobacterium siyangense FTD2, Achromobacter pulmonis NFZ2, and Stenotrophomonas maltophilia FZD2, isolated from a full-scale wastewater treatment plant. Bacterial whole genome sequencing was used for preliminary strain characterization. The metabolomic, electrochemical, and culture methods were applied to understand changes in the bacterial strains after 12-month exposure to nitrofurans. The most significantly altered metabolic pathways were observed in amino acid and sugar metabolism, and aminoacyl-tRNA biosynthesis. Disrupted protein biosynthesis was measured in all strains treated with antibiotics. Prolonged exposure to NFT and FTD also triggered mutagenic effects, affected metabolic activity, and facilitated oxidative stress within the cells. Nitrofuran-induced oxidative stress was evidenced from an elevated activity of catalase and glutathione S-transferases. NFT and FTD elicited similar but not identical responses in all analyzed strains. The results obtained in this study provide new insights into the potential risks of the prolonged presence of antimicrobial compounds in the environment and contribute to a better understanding of the possible impacts of nitrofuran antibiotics on the bacterial cells.PMID:36791847 | DOI:10.1016/j.scitotenv.2023.162199

Biochim Biophys Acta Gen Subj. 2023 Feb 13:130329. doi: 10.1016/j.bbagen.2023.130329. Online ahead of print.ABSTRACTBACKGROUND: Metals are pervasive throughout biological processes, where they play essential structural and catalytic roles. Metals can also exhibit deleterious effects on human health. Powerful analytical techniques, such as mass spectrometry imaging (MSI), are required to map metals due to their low concentrations within biological tissue.SCOPE OF REVIEW: This Mini Review focuses on key MSI technology that can image metal distributions in situ, describing considerations for each technique (e.g., resolution, sensitivity, etc.). We highlight recent work using MSI for mapping trace metals in tissues, detecting metal-based drugs, and simultaneously imaging metals and biomolecules.MAJOR CONCLUSIONS: MSI has enabled significant advances in locating bioactive metals at high spatial resolution and correlating their distributions with that of biomolecules. The use of metal-based immunochemistry has enabled simultaneous high-throughput protein and biomolecule imaging.GENERAL SIGNIFICANCE: The techniques and examples described herein can be applied to many biological questions concerning the important biological roles of metals, metal toxicity, and localization of metal-based drugs.PMID:36791830 | DOI:10.1016/j.bbagen.2023.130329

J Pharm Biomed Anal. 2023 Feb 9;227:115282. doi: 10.1016/j.jpba.2023.115282. Online ahead of print.ABSTRACTCallicarpae Formosanae Folium (CFF), derived from the leaves of Callicarpa formosana Rolfe, is a common Chinese medicinal herb used for the treatment of hematemesis. Phytochemical studies found that phenylpropanoids, flavonoids, terpenoids and polysaccharides were the main ingredients of CFF. However, there is limited scientific information concerning holistic quality method and quality consistency evaluation of CFF. In this study, a strategy integrating HPGPC-ELSD, HPLC-PDA, UV-VIS and UPLC-QTOF-MS/MS was firstly developed to simultaneously qualify and quantify polysaccharides, as well as representative small molecules in CFF. HPGPC-ELSD was applied to characterize the molecular weight distribution of polysaccharides, HPLC-PDA was developed to qualitatively and quantitatively determine monosaccharides. UV-VIS was used to determine the total polysaccharides content, and UPLC-QTOF-MS/MS was established to characterize the small molecules. The quality consistency of commercial CFF (CM-CFF) was also evaluated. It was shown that the relative molecular weights, the compositional monosaccharides and small molecules composition in CM-CFF and self-collected CFF (SC-CFF) samples were similar. A total of 32 small molecules including 6 phenylpropanoids, 7 flavonoids and 19 terpenoids were characterized in CFF. However, the variation was observed in the content of polysaccharides, luteolin, ursolic acid, as well as total contents of terponoids in CM-CFF samples, which implied that the holistic quality of CM-CFF was inconsistent. The results suggested that the proposed evaluation strategy could be applied as a potential approach for the quality control of CFF. And the quality of CM-CFF should be improved by Good Agriculture Practice (GAP) base and standard processing method.PMID:36791651 | DOI:10.1016/j.jpba.2023.115282

Biochem Biophys Res Commun. 2023 Feb 8;651:62-69. doi: 10.1016/j.bbrc.2023.02.018. Online ahead of print.ABSTRACTObesity is a major risk factor for type 2 diabetes, coronary heart disease, and strok. These diseases are associated with profound alterations in gene expression in metabolic tissues. Epigenetic-mediated regulation of gene expression is one mechanism through which environmental factors, such as diet, modify gene expression and disease predisposition. However, epigenetic control of gene expression in obesity and insulin resistance is not fully characterized. We discovered that liver-specific stearoyl-CoA desaturase-1 (Scd1) knockout mice (LKO) fed a high-carbohydrate low-fat diet exhibit dramatic changes in hepatic gene expression and metabolites of the folate cycle and one-carbon metabolism respectively for the synthesis of S-adenosylmethionine (SAM). LKO mice show an increased ratio of S-adenosylmethionine to S-adenosylhomocysteine, a marker for increased cellular methylation capacity. Furthermore, expression of DNA and histone methyltransferase genes is up-regulated while the mRNA and protein levels of the non-DNA methyltransferases including phosphatidylethanolamine methyltransferase (PEMT), Betaine homocysteine methyltransferase (Bhmt), and the SAM-utilizing enzymes such as glycine-N-methyltransferase (Gnmt) and guanidinoacetate methyltransferase (Gamt) are generally down-regulated. Feeding LKO mice a high carbohydrate diet supplemented with triolein, but not tristearin, and increased endogenous hepatic synthesis of oleate but not palmitoleate in Scd1 global knockout mice normalized one carbon gene expression and metabolite levels. Additionally, changes in one carbon gene expression are independent of the PGC-1α-mediated ER stress response previously reported in the LKO mice. Together, these results highlight the important role of oleate in maintaining one-carbon cycle homeostasis and point to observed changes in one-carbon metabolism as a novel mediator of the Scd1 deficiency-induced liver phenotype.PMID:36791500 | DOI:10.1016/j.bbrc.2023.02.018

Mol Genet Metab. 2023 Jan 16;138(3):107509. doi: 10.1016/j.ymgme.2023.107509. Online ahead of print.ABSTRACTPhenylketonuria (PKU, MIM #261600) is one of the most common inborn errors of metabolism (IEM) with an incidence of 1:10000 in the European population. PKU is caused by autosomal recessive mutations in phenylalanine hydroxylase (PAH) and manifests with elevation of phenylalanine (Phe) in plasma and urine. Untreated PKU manifests with intellectual disability including seizures, microcephaly and behavioral abnormalities. Early treatment and good compliance result in a normal intellectual outcome in many but not in all patients. This study examined plasma metabolites in patients with PKU (n = 27), hyperphenylalaninemia (HPA, n = 1) and healthy controls (n = 32) by LC- MS/MS. We hypothesized that PKU patients would exhibit a distinct "submetabolome" compared to that of healthy controls. We further hypothesized that the submetabolome of PKU patients with good metabolic control would resemble that of healthy controls. Results from this study show: (i) Distinct clustering of healthy controls and PKU patients based on polar metabolite profiling, (ii) Increased and decreased concentrations of metabolites within and afar from the Phe pathway in treated patients, and (iii) A specific PKU-submetabolome independently of metabolic control assessed by Phe in plasma. We examined the relationship between PKU metabolic control and extended metabolite profiles in plasma. The PKU submetabolome characterized in this study represents the combined effects of dietary adherence, adjustments in metabolic pathways to compensate for defective Phe processing, as well as metabolic derangements that could not be corrected with dietary management even in patients classified as having good metabolic control. New therapeutic targets may be uncovered to approximate the PKU submetabolome to that of healthy controls and prevent long-term organ damage.PMID:36791482 | DOI:10.1016/j.ymgme.2023.107509

Anal Chem. 2023 Feb 15. doi: 10.1021/acs.analchem.2c05192. Online ahead of print.ABSTRACTMetabolite identification represents a major bottleneck in contemporary metabolomics research and a step where critical errors may occur and pass unnoticed. This is especially the case for studies employing liquid chromatography-mass spectrometry technology, where there is increased concern on the validity of the proposed identities. In the present perspective article, we describe the issue and categorize the errors into two types: identities that show poor biological plausibility and identities that do not comply with chromatographic data and thus to physicochemical properties (usually hydrophobicity/hydrophilicity) of the proposed molecule. We discuss the problem, present characteristic examples, and propose measures to improve the situation.PMID:36791228 | DOI:10.1021/acs.analchem.2c05192

PLoS One. 2023 Feb 15;18(2):e0281594. doi: 10.1371/journal.pone.0281594. eCollection 2023.ABSTRACTHigh-throughput omics technologies have enabled the profiling of entire biological systems. For the biological interpretation of such omics data, two analyses, hypothesis- and data-driven analyses including tensor decomposition, have been used. Both analyses have their own advantages and disadvantages and are mutually complementary; however, a direct comparison of these two analyses for omics data is poorly examined.We applied tensor decomposition (TD) to a dataset representing changes in the concentrations of 562 blood molecules at 14 time points in 20 healthy human subjects after ingestion of 75 g oral glucose. We characterized each molecule by individual dependence (constant or variable) and time dependence (later peak or early peak). Three of the four features extracted by TD were characterized by our previous hypothesis-driven study, indicating that TD can extract some of the same features obtained by hypothesis-driven analysis in a non-biased manner. In contrast to the years taken for our previous hypothesis-driven analysis, the data-driven analysis in this study took days, indicating that TD can extract biological features in a non-biased manner without the time-consuming process of hypothesis generation.PMID:36791130 | DOI:10.1371/journal.pone.0281594

Anal Chem. 2023 Feb 15. doi: 10.1021/acs.analchem.2c03163. Online ahead of print.ABSTRACTPost-translational modifications (PTMs) not only substantially increase structural heterogeneity of proteins but can also alter the conformation or even biological functions. Monitoring of these PTMs is particularly important for therapeutic products, including monoclonal antibodies (mAbs), since their efficacy and safety may depend on the PTM profile. Innovative analytical strategies should be developed to map these PTMs as well as explore possible induced conformational changes. Cation-exchange chromatography (CEX) coupled with native mass spectrometry has already emerged as a valuable asset for the characterization of mAb charge variants. Nevertheless, questions regarding protein conformation cannot be explored using this approach. Thus, we have combined CEX separation with collision-induced unfolding (CIU) experiments to monitor the unfolding pattern of separated mAbs and thereby pick up subtle conformational differences without impairing the CEX resolution. Using this novel strategy, only four CEX-CIU runs had to be recorded for a complete CIU fingerprint either at the intact mAb level or after enzymatic digestion at the mAb subunit level. As a proof of concept, CEX-CIU was first used for an isobaric mAb mixture to highlight the possibility to acquire individual CIU fingerprints of CEX-separated species without compromising CEX separation performances. CEX-CIU was next successfully applied to conformational characterization of mAb glyco-variants, in order to derive glycoform-specific information on the gas-phase unfolding, and CIU patterns of Fc fragments, revealing increased resistance of sialylated glycoforms against gas-phase unfolding. Altogether, we demonstrated the possibilities and benefits of combining CEX with CIU for in-depth characterization of mAb glycoforms, paving the way for linking conformational changes and resistance to gas-phase unfolding charge variants.PMID:36791123 | DOI:10.1021/acs.analchem.2c03163

Clin Transl Oncol. 2023 Feb 15. doi: 10.1007/s12094-023-03097-6. Online ahead of print.ABSTRACTGut microbes are widely considered to be closely associated with colorectal cancer (CRC) development. The microbiota is regarded as a potential identifier of CRC, as several studies have found great significant changes in CRC patients' microbiota and metabolic groups. Changes in microbiota, like Fusobacterium nucleatum and Bacteroides fragilis, also alter the metabolic activity of the host, promoting CRC development. In contrast, the metabolome is an intuitive discriminative biomarker as a small molecular bridge to distinguish CRC from healthy individuals due to the direct action of microbes on the host. More diagnostic microbial markers have been found, and the potential discriminatory power of microorganisms in CRC has been investigated through the combined use of biomic genomic metabolomics, bringing new ideas for screening fecal microbial markers. In this paper, we discuss the potential of microorganisms and their metabolites as biomarkers in CRC screening, hoping to provide thoughts and references for non-invasive screening of CRC.PMID:36790675 | DOI:10.1007/s12094-023-03097-6

Semin Immunopathol. 2023 Feb 15. doi: 10.1007/s00281-022-00982-0. Online ahead of print.ABSTRACTOral mucosal pathologies comprise an array of diseases with worldwide prevalence and medical relevance. Affecting a confined space with crucial physiological and social functions, oral pathologies can be mutilating and drastically reduce quality of life. Despite their relevance, treatment for these diseases is often far from curative and remains vastly understudied. While multiple factors are involved in the pathogenesis of oral mucosal pathologies, the host's immune system plays a major role in the development, maintenance, and resolution of these diseases. Consequently, a precise understanding of immunological mechanisms implicated in oral mucosal pathologies is critical (1) to identify accurate, mechanistic biomarkers of clinical outcomes; (2) to develop targeted immunotherapeutic strategies; and (3) to individualize prevention and treatment approaches. Here, we review key elements of the immune system's role in oral mucosal pathologies that hold promise to overcome limitations in current diagnostic and therapeutic approaches. We emphasize recent and ongoing multiomic and single-cell approaches that enable an integrative view of these pathophysiological processes and thereby provide unifying and clinically relevant biological signatures.PMID:36790488 | DOI:10.1007/s00281-022-00982-0

Plant J. 2023 Feb 15. doi: 10.1111/tpj.16152. Online ahead of print.ABSTRACTWith the increase of global warming and nitrogen oxide emissions, plants have experienced drought and nitrogen (N) deposition. However, little is known about the acclimation to drought and N deposition of Salix species, which are dioecious woody plants. Here, the investigation into foliar N deposition combined with drought was conducted by assessing integrated phenotypes, phytohormones, transcriptomics and metabolomics of male and female Salix rehderiana. The results indicated that there was greater transcriptional regulation in males than in females. Foliar N deposition induced an increase in foliar abscisic acid (ABA) levels in males, resulting in the inhibition of stomatal conductance, photosynthesis, carbon (C) and N accumulation and growth, whereas more N was assimilated in females. Growth as well as C and N accumulation in drought-stressed S. rehderiana females increased after N deposition. Interestingly, drought decreased flavonoid biosynthesis whereas N deposition increased it in females. Both drought and N deposition increased flavonoid methylation in males and glycosylation in females. However, for drought-suffered S. rehderiana, N deposition increased the biosynthesis and glycosylation of flavonoids in females but decreased glycosylation in males. Therefore, foliar N deposition affects the growth and drought tolerance of S. rehderiana by altering the foliar ABA levels and the biosynthesis and modification of flavonoids. This work provides a basis for understanding how S. rehderiana may acclimate to N deposition and drought in the future.PMID:36790349 | DOI:10.1111/tpj.16152

Microbiol Spectr. 2023 Feb 15:e0320922. doi: 10.1128/spectrum.03209-22. Online ahead of print.ABSTRACTBased on the structural modification of SM21, xy12, a new pyrylium salt derivative with enhanced antifungal activities, was synthesized. The MICs (MIC90) of xy12 against Candida albicans ranged from 0.125 to 0.25 μg/mL, about 2-fold lower than those of SM21. In addition, xy12 inhibited hypha and biofilm formation in C. albicans in a dose-dependent manner. A total of 3,454 differentially expressed genes and 260 differential metabolites were identified in the xy12-treated C. albicans by RNA-seq and non-targeted metabolomics. By integrating KEGG pathway enrichment analysis, we found that inhibition of oxidative phosphorylation was the important antifungal mechanism of action of xy12. Electron transport through mitochondrial respiratory complexes I to IV is the common process of oxidative phosphorylation. Compared with the sensitivity of the wild-type SC5314 to xy12, decreased sensitivities in mitochondrial complex I (CI)-deficient mutants and increased sensitivities in mitochondrial complex III- and IV-deficient mutants suggested that the antifungal effects of xy12 were dependent on CI. Consistently, xy12 exhibited antagonism with rotenone, an inhibitor of CI, and significantly inhibited the expression and activity of CI. Meanwhile, the phenotypes in the xy12-treated C. albicans were similar to those in the CI-deficient mutants, such as decreased ATP production, reduced mitochondrial membrane potential, loss of mitochondrial DNA, inability to utilize nonfermentative carbon sources, and decreased cell wall N-linked mannoproteins. Collectively, our results revealed that the pyrylium salt xy12 could constrain oxidative phosphorylation by inhibiting mitochondrial complex I in C. albicans, providing a novel lead compound for the development of mitochondria-targeted antifungal drugs. IMPORTANCE The development of new antifungal drugs is critical for solving the problem of antifungal resistance and expanding the limited variety of clinical antifungal drugs. Based on the modification of the pyrylium salt SM21, a new lead compound, xy12, was synthesized which was effective against Candida species both in vitro and in vivo. In this study, conjoined analysis of the transcriptome and metabolome elucidated the antifungal mechanism of action of xy12, which inhibited the activity of mitochondrial complex I in C. albicans. Targeting fungi-specific mitochondrial complex proteins has been reported as a promising antifungal strategy. Our study provided a new lead compound for targeting C. albicans mitochondrial complex I, which could be beneficial for discovering novel antifungal drugs.PMID:36790175 | DOI:10.1128/spectrum.03209-22